Child stunting is an indicator of chronic undernutrition and reduced human capital. However, it remains a poorly understood public health problem. Small-quantity lipid-based nutrient supplements (SQ-LNS) have been widely tested to reduce stunting, but have modest effects. The infant intestinal microbiome may contribute to stunting, and is partly shaped by mother and infant histo-blood group antigens (HBGA). We investigated whether mother-infant fucosyltransferase status, which governs HBGA, and the infant gut microbiome modified the impact of SQ-LNS on stunting at age 18 months among Zimbabwean infants in the SHINE Trial (NCT01824940). We found that mother-infant fucosyltransferase discordance and Bifidobacterium longum reduced SQ-LNS efficacy. Infant age-related microbiome shifts in B. longum subspecies dominance from infantis, a proficient human milk oligosaccharide utilizer, to suis or longum, proficient plant-polysaccharide utilizers, were partly influenced by discordance in mother-infant FUT2+/FUT3-phenotype, suggesting that a “younger” microbiome at initiation of SQ-LNS reduces its benefits on stunting.

The authors have declared no competing interest.

NCT01824940

Funding was from the Bill & Melinda Gates Foundation (OPP1021542 and OPP1143707; J.H.H. and A.J.P.), with a subcontract to the University of British Columbia (20R25498; A.R.M.). United Kingdom Department for International Development (DFID/UKAID; J.H.H. and A.J.P.). Wellcome Trust (093768/Z/10/Z, 108065/Z/15/Z, 206455/Z/17/Z, 203905/Z/16/Z and 210807/Z/18/Z; A.J.P., R.C.R. and C.E.). Swiss Agency for Development and Cooperation (J.H.H. and A.J.P.). US National Institutes of Health (2R01HD060338-06; J.H.H.). UNICEF (PCA-2017-0002; J.H.H. and A.J.P.). The Nutricia Research Foundation (2021-52; E.K.G.) The funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Medical Research Council of Zimbabwe (MRCZ/A/1675), Johns Hopkins Bloomberg School of Public Health (JHU IRB # 4205.), and the University of British Columbia Ethics Board (H15-03074) approved the study protocol, including the microbiome analyses. The SHINE trial is registered at ClinicalTrials.gov (NCT01824940).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.